Beta-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin-linked kinase

Can J Physiol Pharmacol. 2010 Aug;88(8):796-801. doi: 10.1139/Y10-052.


The contribution of the endothelin-1 (ET-1)/ET A receptor (ETAR) axis in tumor growth and progression is investigated in many tumor types, including ovarian carcinoma. In ovarian cancer cells, ET-1 acts as an autocrine growth factor selectively through the ETAR triggering the concomitant activation of multiple pathways. In these cells, the involvement of beta-arrestin-1 as signal transducer in ET-1-dependent signalling pathways has been recently highlighted. Because several G protein-coupled receptors have been shown to activate signalling pathways in a beta-arrestin-dependent manner, in this study we explored whether beta-arrestin-1 is involved in a distinct signalling mechanism linking the ETAR to phosphoinositide 3-kinase (PI3K)/integrin-linked kinase (ILK)/Akt in HEY ovarian cancer cells. The inhibitory effects of ZD4054 (zibotentan), a specific ETAR antagonist, in ET-1-dependent phosphorylation of ILK, Akt, and glycogen synthase kinase (GSK-3beta) demonstrated the involvement of the ETAR in these effects. By using a kinase assay, we demonstrate that beta-arrestin-1 silencing inhibits the ET-1-induced ILK activity in a time-dependent manner and downstream Akt and GSK-3beta phosphorylation. These results reveal that beta-arrestin-1 is implicated as an ETAR-transducer in the activation of ILK and Akt and in the inactivation of GSK-3beta in response to ET-1 and further support the role of beta-arrestin-1 as a multifunctional adaptor facilitating interprotein interactions critically involved in ETAR-mediated signalling that regulate invasive and metastatic behaviour of ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrestins / genetics
  • Arrestins / metabolism*
  • Cell Line, Tumor
  • Endothelin A Receptor Antagonists*
  • Endothelin-1 / pharmacology*
  • Enzyme Activation / drug effects
  • Female
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Models, Biological
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyrrolidines / pharmacology
  • RNA, Small Interfering / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • beta-Arrestin 1
  • beta-Arrestins


  • ARRB1 protein, human
  • Arrestins
  • Endothelin A Receptor Antagonists
  • Endothelin-1
  • Pyrrolidines
  • RNA, Small Interfering
  • ZD4054
  • beta-Arrestin 1
  • beta-Arrestins
  • integrin-linked kinase
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3